Washington Editor

GAITHERSBURG, Md. - A panel of experts Wednesday narrowly backed the approval of Dyax Corp.'s Kalbitor (ecallantide, DX-88) to treat acute attacks of hereditary angioedema (HAE), a rare, genetic disorder, despite the drug's potential to cause severe allergic reactions and a lack of robust study data.

In a 6-to-5 vote, with two abstentions, the FDA's Pulmonary-Allergy Drugs Advisory Committee said Dyax's studies for Kalbitor, a recombinant plasma kallikrein inhibitor, provided substantial and convincing evidence to support the drug's approval.

Acting Chairman William Calhoun, an internal medicine professor at the University of Texas, said he would not call the panel's vote "split," given the outcome of the other votes taken Wednesday.

While the panel voted 8 to 4 that there was strong evidence of a clinically meaningful benefit of the drug in adults 18 years or older, the committee said in an 11-to-2 vote that Dyax had failed to provide the same level of evidence for the effectiveness of Kalbitor in children and adolescents.

Dyax is seeking approval of the medication in children as young as 10 years.

But many on the panel argued that because HAE is a rare disease - affecting 1 in about every 10,000 people in the U.S., with some estimates at 1 in every 50,000 - with attacks occurring in a unpredictable and intermittent manner, it would be difficult for Dyax to collect sufficient and compelling study data in children.

"It will never happen," said panelist Lawrence Borish, an allergist and professor of medicine at the University of Virginia in Charlottesville.

Panelist Richard Honsinger, a physician at the Los Alamos Medical Center Clinic in New Mexico, argued that "there's no reason to think children are any different in this disease than adults."

The committee also said the drug's safety had not been adequately assessed in children or adults and called Dyax's proposed risk management plan insufficient to protect patients.

Of 219 patients who received Kalbitor in studies, eight, or 3.7 percent, experienced a severe anaphylactic reaction, said Susan Limb, a medical officer in the FDA's Division of Pulmonary and Allergy Products. Such reactions can be unpredictable and may be life-threatening events, she added.

However, Dyax disputed the FDA's analysis and said that half of those anaphylaxis cases were actually other less severe types of hypersensitivity reactions.

There currently are no treatments approved in the U.S. for acute HAE, an orphan indication. However, the FDA last year approved ViroPharma Inc.'s Cinryze (C1-esterase inhibitor) as a prophylactic therapy for the condition. (See BioWorld Today, Oct. 14, 2008.)

ViroPharma, which acquired the rights of Cinryze through its acquisition last year of Lev Pharmaceuticals Inc., submitted a supplemental biologics license application in December 2008 for Cinryze to treat acute attacks of HAE. (See BioWorld Today, July 16, 2008.)

Dyax submitted two efficacy studies to the FDA, known as EDEMA3 and EDEMA4, for its BLA. However, the data for EDEMA3 were not considered robust by the agency, and there was an accidental administration of placebo to one patient assigned to Kalbitor and a patient who was supposed to get placebo got Kalbitor. Dyax later reanalyzed the data. (See BioWorld Today, Feb. 4, 2009.)

Some on the panel argued in favor of the drug's approval because it would fill an unmet medical need to treat an orphan indication.

HAE causes not only unpredictable swelling of the face, gastrointestinal tract, limbs and genitalia, but also the larynx, which can be deadly.

But Mark Ballow, chief of the Division of Allergy and Immunology at Women and Children's Hospital of Buffalo, N.Y., said that the FDA "cannot lower the bar" by setting a different standard for safety and efficacy for orphan drugs than that set for all other medications.

"The FDA has gotten in trouble before for lowering the bar, and it has come back to haunt them," he declared.

Ballow called for more studies of Kalbitor.

Many others on the panel also said that better assays need to be developed and used to help identify patients more prone to allergic reactions. In addition, several of the experts said that epinephrine should be readily available at clinics where Kalbitor is administered.

The FDA is set to make a decision on Kalbitor next month.

Trading of shares for Dyax (NASDAQ:DYAX) was suspended Wednesday.

Published  February 5, 2009